PROJECT SUMMARY This is a training award to support Dr. Goldfine in his development to become an independent clinical investigator studying the role of the brain's arousal systems in recovery from stroke and traumatic brain injury. Arousal is an important target for stroke recovery, as brain systems supporting it excite neurons widely, and can thereby enhance recovery across a wide range of impairments. During this award period, Dr. Goldfine will undertake formal training in the systems neuroscience of arousal mechanisms, along with quantification of behavioral and cognitive deficits typically associated with impaired arousal. He will also learn how to use quantitative analysis of MRI and electroencephalography (qEEG) to characterize brain function at the network level. To support this training, Dr. Goldfine will conduct a mentored research project on the pathophysiology of post-stroke apathy. Apathy, also known as abulia, is a reduction of goal-directed behavior beyond expected from motor dysfunction and not due to somnolence. Apathy is common after stroke (35% of patients) and associated with worse disability, slower rate of recovery, and need for institutional care. There is currently no treatment, and the underlying pathophysiology of apathy is not known. Here, Dr. Goldfine will test a model that reduction of goal-directed behavior can be due to dysfunction of the brain's arousal regulation system - medial prefrontal cortex, anterior cingulate, and connected areas of basal ganglia and central thalamus. He will test the model across two aims: 1) by measuring function of the arousal regulation network using qEEG and an MRI measure of blood flow; and 2) by determining if activation of the arousal regulation system with amantadine improves apathy. Dr. Goldfine will first conduct a cross-sectional study, comparing qEEG and MRI in subjects with stroke with, versus without apathy. Dr. Goldfine will then conduct a placebo-controlled trial of amantadine in subjects with post-stroke apathy who are undergoing acute rehabilitation. In the trial, the qEEG measure from the cross-sectional study will be used to determine if resolution of apathy is associated with improved function of the arousal regulation system. The improved understanding of the neuronal dysfunction underlying post-stroke apathy obtained from this work will provide scientists and clinicians with treatment targets and diagnostic tests to improve outcomes in patients with post-stroke apathy.